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Cucurbitacin B Inhibits Cell Proliferation and Induces Apoptosis in Human Osteosarcoma Cells Via Modulation of the JAK2/STAT3 and MAPK Pathways

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Cucurbitacin B Inhibits Cell Proliferation and Induces Apoptosis in Human Osteosarcoma Cells Via Modulation of the JAK2/STAT3 and MAPK Pathways EXPERIMENTAL AND THERAPEUTIC MEDICINE 14: 805-812, 2017 Cucurbitacin B inhibits cell proliferation and induces apoptosis in human osteosarcoma cells via modulation of the JAK2/STAT3 and MAPK pathways ZHI-REN ZHANG1, MING-XIA GAO2 and KAI YANG3 1Department of Orthopedics, Zhumadian Central Hospital, Zhumadian, Henan 463600; 2Department of Health Management, Dongying People's Hospital, Dongying, Shandong 257000; 3Department of Joint Surgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan 450007, P.R. China Received October 20, 2015; Accepted February 27, 2017 DOI: 10.3892/etm.2017.4547 Abstract. Osteosarcoma (OS) is the most commonly diagnosed Introduction tumor of the bones in children and young adults. Even with conventional therapies the 5-year survival rate is ~65% in Osteosarcoma (OS) a primary sarcoma of the bones that patients with OS. Considering the side effects and aggres- primarily affects children and adolescents accounting for ~5% siveness of malignant bone tumors, research is focussing on of pediatric tumors (1). OS affects the distal long bones, the multi-targeted strategies in treatment. Cucurbitacin B, a triter- femur and tibia (1) and is generally characterized by its local penoid compound has been demonstrated to induce apoptosis invasion of bone and soft tissues, loss of the affected extremity's in various cancer cell types. The Janus kinase 2/signal trans- functions and distant metastasis (2). Multimodal conventional ducer and activator of transcription 3 (JAK2/STAT3) signalling therapies including radiation, surgical resection and chemo- cascades and mitogen activated protein kinases (MAPK) therapy are employed to treat OS (3,4). Despite the combination signalling cascades are critical regulators of tumorigenesis. therapy approach, limited improvement has been observed in the The present study assessed the influence of cucurbitacin B 5-year survival rate (65%) of patients with OS (5). Furthermore, on the viability and expression of MAPKs and proteins of these therapeutic approaches often lead to severe side effects the JAK2/STAT3 cascades in human OS cells (U-2 OS). such as cardiotoxicity, hearing loss and nephrotoxicity, and Cucurbitacin B (20‑100 µM) significantly reduced cell viability may also cause drug resistance and increase the risk of local (P<0.05) and induced apoptosis, as assessed by MTT and relapse (6). Thus, improved targeted approaches are required, Annexin V/propidium iodide staining, along with inhibiting with no or less side effects. cell migration. Gelatin zymography revealed supressed activi- The Janus kinase 2 (JAK2)/signal transducer and activator of ties of matrix metalloproteinase (MMP-)2 and 9. Furthermore, transcription 3 (STAT3) signalling pathway serves a critical role cucurbitacin B effectively upregulated the apoptotic pathway in cell survival and division. Activated JAK2/STAT3 signalling and caused the effective inhibition of MAPK signalling and cascade influences the expression of numerous proteins that JAK2/STAT3 cascades. Multifold suppression of vascular are associated with various physiological functions, including endothelial growth factor by cucurbitacin B was also observed, cell cycle regulation and apoptosis. The JAK/STAT3 pathway indicating inhibition of angiogenesis. Thus, by downregu- regulates the expression level of anti-apoptotic proteins [B-cell lating major pathways-MAPK and JAK2/STAT3 and MMPs, lymphoma-extra large (Bcl-xL) and myeloid leukemia cell cucurbitacin B has potent anti-proliferative and anti-metastatic differentiation protein (Mcl-1)] (7), cell cycle regulatory proteins effects that require further investigation with regards to cancer (cyclin D1, p21, and p27) (8) and mitochondrial apoptosis treatment. pathway related proteins [Bcl-2 associated X (Bax), cyto- chrome c and caspase-3] (9). Furthermore, STAT3 activation promotes angiogenesis by inducing vascular endothelial growth factor (VEGF) (10), and also stimulates invasion and metastasis by increasing the expression of matrix metalloproteinases Correspondence to: Dr Kai Yang, Department of Joint Surgery, (MMPs) (11). The pathway is considered as a major molecular Zhengzhou Central Hospital Affiliated to Zhengzhou University, 195 Tongbai Road, Zhengzhou, Henan 450007, P.R. China target of interest in a number of cancer types, including mela- E-mail: [email protected] noma (12), renal carcinoma (13) and breast cancer (14). The mitogen-activated protein kinases (MAPKs) signalling Key words: apoptosis, cucurbitacin, Janus kinase/signal transducer cascades are a large family of serine/threonine kinases that and activator of transcription pathway, mitogen activated protein control and regulate various physiological process, including cell kinases, osteosarcoma survival and apoptosis, and are also involved in tumorigenesis. The functions of MAPK signalling in cancer development are complex, as they regulate wide range of cellular responses (15). 806 ZHANG et al: CUCURBITACIN B INDUCES APOPTOSIS OF HUMAN OSTEOSARCOMA CELLS Activated MAPK pathway stimulates cell growth or induces Measurement of cell viability. OS cells were seeded into apoptosis based on the stimuli (16,17). Numerous studies have 96-well plates (5x105 cells/well) and incubated at 37˚C for reported that the c-Jun N-terminal kinases (JNK), p38 and 24 h. On reaching 70% confluence, the cells were treated extracellular signal-regulated kinases (ERK1/2) cascades exert with different concentrations of cucurbitacin B (20, 40, 80 a vital role in regulating cytotoxic drug induced apoptosis in and 100 µM) for 24 h. Cells were then incubated at 37˚C with OS (18,19). Thus, targeting the pathway may have clinical value MTT for 4 h. The formazan crystals formed were dissolved in the treatment of OS. with dimethyl sulfoxide and the absorbance was measured at Accumulating research data indicate that plant-derived 570 nm using a Thermo Multiskan Spectrum (Thermo Fisher compounds are much more effective in inhibiting cancer cell Scientific, Inc., Waltham, MA, USA). proliferation and inducing apoptosis (20). Phytochemicals are reported to elicit antitumor effects by inducing cellular defense Analysis of apoptosis by Annexin V assay. OS cells were incu- system, antioxidant enzymes system and also inhibition of bated at 37˚C with various concentrations of cucurbitacin B anti‑cell growth signalling and anti‑inflammatory pathways (20, 40, 80 and 100 µM) for 24 h. Following incubation, culminating in apoptosis and/or cell cycle arrest (21-24). cells were treated with 0.25% trypsin, washed twice with Cucurbitacins were initially identified in the Cucurbitaceae ice-cold PBS and harvested for detection of apoptosis using plant family, which includes cucumber and are also isolated an Annexin V-FITC apoptosis detection kit (BD Biosciences, from various plant families (25). Owing to their effective phar- Franklin Lakes, NJ, USA), according to the manufacturer's macological properties, plants rich in cucurbitacins have been instructions. The cells were washed in PBS at 1x106 cells/ml widely used in traditional Chinese medicine for their analgesic, and suspended at 1x105/100 µl binding buffer (BD Biosciences) anti‑inflammatory, antimicrobial, antipyretic, antitumor activities containing FITC-conjugated anti-Annexin V antibody and hepatoprotective effects (25-28). Researchers have reported (provided in the kit) and PI, and analyzed for fluorescence that cucurbitacin I may inhibit cancer cell growth by disrupting using a flow cytometer (FACSCalibur; BD Biosciences). the JAK/STAT3 signaling pathway in both in vitro and in vivo tumor models (29,30). Studies have reported that cucurbitacin B Determination of morphological changes by Hoechst inhibits the growth of various human cancer cell lines and tumor staining. Morphological changes of the U-2 OS cells following xenografts including breast, prostate, lung, uterine cervix, liver, treatment with cucurbitacin B was determined by Hoechst skin and brain cancer (18,31,32). Considering the biological staining. Briefly, the OS cells were seeded at a density of effects cucurbitacin B, the present study aimed investigate the 5x104 cells per well in a 6‑well plate and cultured at 37˚C for effects of cucurbitacin B on human OS cells and assess whether 12 h and treated with cucurbitacin B (20, 40, 80 and 100 µM) it modulates the JAK/STAT3 and MAPK signalling pathways. for 48 h. The cells were then fixed with 4% paraformalde- hyde in PBS for 10 min, washed with PBS and stained with Materials and methods Hoechst 33258 (5 mg/l) for 15 min at room temperature in the dark. The cells were observed under a a fluorescence Reagents and chemicals. Cucurbitacin B, glutamine, microscope (Nikon Eclipse TiS coupled with NIS-Elements RPMI 1640 medium, fetal calf serum (FCS), penicillin, strepto- imaging software; Nikon Corporation, Tokyo, Japan). The mycin and 0.25% trypsin were purchased from Sigma Aldrich; cells undergoing apoptosis were characterized by condensed Merck KGaA (Darmstadt, Germany). Antibodies against or fragmented nuclei. ERK1/2 (cat. no. 9102), phospho-ERK1/2 (cat. no. 9101), p38 (rabbit mAb, cat. no. 8690), phospho-p38 (rabbit mAb, cat. Wound healing assay. The influence of cucurbitacin B on no. 4511), JNK (cat. no. 9252), phospho-JNK (mouse mAb, the cell migration of U-2 OS cells was assessed. In brief, cat. no. 9255), MMP-2 (rabbit mAb, cat. no. 87809), MMP-9 5x105 cells were maintained in 10 cm Petri plates and incu- (cat. no. 852) (all from Cell Signaling Technology, Danvers, bated
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